Bis(alkoxyphenyl)pyrroles and pyrrolines



United States Patent Office Patented Dec. 29, 1970 Int. Cl. (307d 27/22U.S. Cl. 260326.3 3 Claims ABSTRACT OF THE DISCLOSURE Disclosed arebis(a1koxyphenyl)pyrroles and pyrrolines useful as central nervoussystem depressants in animals and as sun-screening agents.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisionof U.S. Ser. No. 544,847, filed on Apr. 25, 1966, now U.S. Pat. No.3,462,451.

BACKGROUND OF THE INVENTION This invention is directed to five-memberN-heterocycles which contain nuclear unsaturation. It has now been foundthat certain such compounds exhibit central nervous system depressantactivity and also are effective as sunscreening agents.

SUMMARY OF THE INVENTION The compounds contemplated herein are fivemember N-heterocycles having a partially or completely unsaturatednucleus and represented 'by the structural formula i OR structuralformula H OR (II) wherein the substitutents Z and R are as indicatedabove.

Also contemplated within the purview of the present invention are thebis(alkoxyphenyl)-l-pyrrolines which can be represented by thestructural formula wherein the R substituent is as indicated above.

(III) The compounds represented by Formula III can also exist in theprotonated or acid addition salt form. Stable acid addition salts can beformed on neutralization of the bis(alkoxyphenyl)-1-pyrrolines withacids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric,acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric,maleic, malic, pamoic, methanesulfonic, picric, cyclohexanesulfamic,lactic, and the like.

DETAILED DESCRIPTION OF THE INVENTION Several methods are available forthe preparation of the compounds of this invention. One method involvesthe condensation of a dialkyl acetylenedicarboxylate with an aminoketonerepresented by the structural formula OR (IV) where R is as indicatedabove.

The latter can be prepared in accordance with the teachings of Drefahlet al., Ann. 589, 82 (1954). The condensation can be carried out in alower aliphatic alcohol such as methanol, ethanol, the propanols, or thebutanols (preferably methanol) as a solvent at a temperature in therange of from about 25 C. to about C. and preferably from about 50 C. toabout 80 C. The reaction time can vary from about 15 minutes to about 24hours. The procedural steps employed in the preparation are similar tothose employed by Hendrickson et al., J. Amer. Chem. Soc. 83, 1250(1961) and in J. Amer. Chem. Soc. 86, 107 (1964).

The resulting end product from the condensation is a dialkyl4,5-bis(alkoxyphenyl)pyrrole 2,3 dicarboxylate which can be hydrolyzedin the presence of an alkali metal hydroxide, e.g., sodium or potassiumhydroxide, or the like, to produce the corresponding4,5-bis(alkoxyphenyl) pyrrole-2,3-dicarboxylic acid which, in turn, canbe decarboxylated by heating to a temperature in the range from about C.to about 250 C. and preferably from about 200 C. to about 230 C. so asto produce a 2,3-'bis(alkoxyphenyl)pyrrole. The aforedescribed syntheticroute is illustrated below in the preparation of2,3-bis(p-methoxyphenyl)pyrrolez Another method of preparation of thecompounds of this invention comprises the reaction of a desoxybenzoinhaving the structural formula HOOC where R is as indicated above, withformaldehyde and a secondary amine either in the free base form or theacid addition salt form to produce the corresponding 1,2-bis(alkoxyphenyl)-3-dialkylamino-l-propanone. The reaction can be carriedout in the presence of an inert reaction medium and at a temperature inthe range from about 50 C. to about 150 C. This preparation is fully setforth in British Pat. 828,762. The thus obtained reaction product canthen be condensed with nitromethane in the presence of a sodium orpotassium alkoxide, containing up to about four carbon atoms in thealkyl portion thereof, at a temperature in the range from about 40 C. toabout 100 C., and thereafter reduced by catalytic hydrogenation in thepresence of Raney nickel catalyst to produce a2.3-bis(alkoxyphenyl)-l-pyrroline. The pyrroline compound can then bedehydrogenated at a temperature in the range from about 150 C. to about250 C. by using catalytic amounts of a palladium catalyst on a suitablecarrier. A solvent such as Decalin, p-cymene, or

the like, can be employed in the latter step. The synthetic route isschematically illustrated below in the preparation of2,3-bis(p-methoxyphenyl)pyrrole:

The compounds of this invention are useful as central nervous systemdepressants in animals. Their pharmacological activity has beenestablished through tests in rats of2.3-bis(p-methoxyphenyl)-l-pyrroline.

4,5-bis(p-methoxyphenyl)pyrrole-2,3-dicarboxylic acid,

dimethyl 4,5-bis(p-rnethoxyphenyl)pyrrole-2,3-dicarboxylate, and

2,3-bis (p-methoxyphenyl pyrrole.

addition, the compounds can be incorporated in a pharmaceuticallyacceptable carrier and used as a cream, oil, ointment, or the like, tominmize sunburn.

According to the type of material treated, to the requirements ofeffectiveness and durability and other contingencies, the amount of thecompound absorbing ultraviolet light may vary within relatively widelimits. For example, for sunburn prevention, from about 0.5% to about 5%by weight of the substrate to be protected, can be the useful range.

This invention is further illustrated by the following examples:

EXAMPLE I Preparation of dimethyl 4,5-bis(p-methoxyphenyl)pyrrole-2,3-dicarboxylate A mixture of2-amino-4'-methoxy-2-(p-methoxyphenyl) acetophenone hydrochloride (about176 grams, 0.573 mole), dimethyl acetylenedicarboxylate (about 81.5grams, 0.573 mole), sodium acetate (about 47 grams, 0.573 mole), andmethanol (about 1440 milliliters) was placed in a reaction vessel andrefluxed for about 15 minutes. Thereafter, the mixture was cooled, 4 Nmethanolic hydrogen chloride (about 1440 milliliters) was added, and therefluxing continued for about one-half hour.

The refluxing was then terminated and the resulting admixture wasevaporated to dryness with stirring in vacuo at about 40 C. The residuethus obtained was then diluted with water (about 1 liter) and stirred soas to produce a suspension. The suspension was then filtered and ayellow solid recovered. The yellow solid was washed with water (about200 milliliters). Thereafter, a suspension of the washed yellow solidwas prepared in Water (about 2 liters) and heated on a steam bath whilebeing agitated until all of the starting materials still present wentinto solution. While hot, the suspension was filtered and a yellowprecipitate was recovered.

The yellow precipitate was then washed with hot water (about 200milliliters), dissolved in methanol (about 2.6 liters), the resultingsolution filtered, evaporated to a volume of about 1.2 liters, andcooled while being swirled. A yellow solid (about 29 grams) crystallizedout of the methanol solution upon cooling, having a melting point ofabout l90-l92 C. Upon recrystallization from methanol, the melting pointwas raised to about 192-193 C. A second crop of the yellow solid (about1.9 grams) was obtained subsequently from the filtrate, having a meltingpoint of about 189-191 C.

The yellow solid was identified as dimethyl 4,5-bis(pmethoxyphenyl)pyrrole 2,3 dicarboxylate obtained in about 14% yield.

Analysis.Calc'd for C H NO (percent): C, 66.82; H, 5.35; N, 3.54. Found(percent): C, 67.13; H, 5.52; N. 3.64.

U.V. absorption spectrum in ethanol:

k 23fi my. (e:22,800) Sh. 260 mp. (6 15,300) sh. 283 m [e216,000) sh.303 mg (6 18.550) 310 mu (6:18.650)

with methanol (about 580 milliliters), and with a 20 weight percentaqueous solution of sodium hydroxide (about 580 milliliters). Theresulting admixture was heated under nitrogen on a steam bath whilebeing stirred. After about five minutes of heating, the admixture beganrefluxing and a solution was obtained.

After an additional five minutes of refluxing, the solution was observedto have changed into a relatively thick suspension. The refluxing wasthen continued for about five additional minutes, and thereafter, themethanol was distilled off. The remaining aqueous suspension was cooledon ice and acidified with concentrated hydrochloric acid (about 300milliliters). During cooling, a solid precipitate was formed.

The solid precipitate was filtered off and washed with water. Duringwashing, the solid precipitate turned oily. The oily solid was thencrystallized from acetic acid (about 50 milliliters) and water (about120 milliliters). About 25.7 grams of a pale yellow product wasobtained, having a melting point of about 202204 C. (dec.). The meltingpoint did not change upon recrystallization from a benzene-acetonesolution.

The thus prepared pale yellow product was identified as4,5-bis(p-methoxyphenyl)pyrrole-2,3-dicarboxylic acid obtained in about95% yield.

Analysis.Calcd for C20H17NO6 (percent): C, 65.39; H, 4.66; N, 3.81.Found (percent): C, 65.46; H, 4.75; N, 3.97.

U.V. absorption spectrum in ethanol:

281 mp. $14,400 sh. 296 m $12,850 sh. 318 mu 6:9,950

U.V. absorption spectrum in 0.01 N alcoholic acid:

A =238 mp. (e=24,400)

sh. 270 mp (e: 14,100) 329 mp. (e=9,900)

U.V. absorption spectrum in 0.01 N alcoholic base:

A =23l mp. (e=14,800)

257.5 mg (e=19,700) 288 m,u. (e=l7,700) 298 mp. (e=18,700)

In a similar manner, dibutyl 4,5-bis(o-ethoxyphenyl)pyrrole-Z,3-dicarboxylate can be hydrolyzed to4,5-bis(oethoxyphenyl)pyrrole-2,3-dicarboxylic acid, diethyl4-(ppropoxyphenyl) 5 (p butoxyphenyl)pyrrole 2,3 dicarboxylate can behydrolyzed to 4-(p-propoxyphenyl)-5-(p-butoxyphenyl)pyrrole-2,3-dicarboxylic acid, dimethyl 4 (pbutoxyphenyl) 5 (m ethoxyphenyl)pyrrole- 2,3-dicarboxylate can behydrolyzed to4-(p-butoxyphenyl)-5-(m-ethoxyphenyl)pyrrole-2,3-dicarboxylic acid, etc.

EXAMPLE III Preparation of 2,3-bis(p-methoxyphenyl)pyrrole4,5-bis(p-methoxyphenyl)pyrrole-2,3-dicarboxylic acid (about 24.16grams, 0.066 mole) was heated in an oil bath and under nitrogen at atemperature of about 200 to 220 C. (oil bath temperature) for abouttwenty minutes. Thereafter, the obtained reaction product was distilledoff in an oil-jacketed flask at about 240 to 255 C. (oil bathtemperature) and about 0.2 to 0.5 mm. of Hg pressure. About 12.91 gramsof distillate in the form of a yellow oil was recovered.

The yellow oil was dissolved in diethyl ether (about 200 milliliters).The resulting solution was washed with a 5 weight percent aqueous sodiumhydroxide solution (with two aliquots, about 100 milliliters each), thenwith water, and with a saturated sodium chloride solution. The washedsolution was then dried by passing through sodium sulfate andthereafter, the diethyl ether evaporated.

The thus obtained residue (about 12.8 grams) was dissolved in a 20volume percent ethyl acetate-cyclohexane solution (about 200milliliters) and chromatographed on silica gel (about 756 grams).Elution with the same solvent (about 3.5 liters) yielded about 12.56grams of product. This product was then crystallized from petroleumether (boiling range about 30 to 60 C.) with seeding. About 5 grams ofprismatic crystals were obtained upon filtering having a melting pointof about 68 to 69.5 C. The melting point did not change uponrecrystallization.

The petroleum ether filtrate was evaporated to dryness, the residuedissolved in a 20 volume percent ethyl acetate-cyclohexane solution,passed through a column of silica gel (about 15 grams), eluted, and theeluate crystallized as before. The entire operation was performed asquickly as possible so as to avoid reddening of the resultingcrystalline product. Additional 3.9 grams of pink crystals having amelting point of about 6870 C. was obtained.

The crystalline product obtained in the aforedescribed manner wasidentified as 2,3-bis(p-methoxyphenyDpyrrole, in about 49 percent yield.

Analysis.Calcd for C H NO (percent): C, 77.39; H, 6.13; N, 5.01. Found(percent): C, 76.93; H, 6.55; N, 4.73.

U.V. absorption spectrum in ethanol:

k =247 mp. (e=20,100)

294.5 m (e=l5,l50)

In a similar manner, 4,5-bis(o-ethoxyphenyl)pyrrole- 2,3-dicarboxylicacid can be decarboxylated to 2,3-bis(oethoxyphenyl pyrrole, 4-(p-propoxyphenyl) -5- (p-butoxyphenyl)pyrrole-2,3-dicarboxylic acid canbe decarboxylated to 2-(p-butoxyphenyl)-3-(p-propoxyphenyl)pyrrole, 4 (pbutoxyphenyl) 5 (m ethoxyphenyl)pyrrole- 2,3-dicarboxylic acid can bedecarboxylated to 2-(methoxyphenyl -3- (p-butoxyphenyl) pyrrole, etc.

EXAMPLE IV Preparation of 2,3-bis(p-methoxyphenyl)-l-pyrroline 1,2 bis(pmethoxyphenyl) 3 dimethylamino lpropanone hydrochloride (about 42.6grams, 0.122 mole) was released to the free base. A mixture Was thenprepared of the free base, nitromethane (about 213 milliliters), andsodium methoxide (about 0.77 gram), in a suitable reaction vessel andrefluxed with stirring for about six hours. A stream of nitrogen waspassed through the mixture during refluxing.

The refluxed mixture was then permitted to stand for about 15 hours.Thereafter, water (about milliliters) was added and the resultingadmixture was extracted twice with diethyl ether.

The resulting ether extract was washed with a 10 weight percent aqueoushydrochloric acid solution (three aliquots, about 50 milliliters each),a saturated sodium chloride solution, and then dried by passing throughsodium sulfate. Thereafter, the ether was evaporated from the driedether extract and a crude oil (about 50.1 grams), was obtained.

The crude oil was dissolved in ethanol (about 1500 milliliters) andhydrogenated in the presence of about four teaspoons of Raney nickelcatalyst at an initial pressure of about 30 p.s.i.g. After about threehours, the hydrogen uptake was observed to have stopped, and thehydrogenation was discontinued.

The resulting mixture was filtered through diatomaceous earth and thefiltrate evaporated. Evaporation of the filterate produced a residuewhich was dissolved in diethyl ether (about 1 liter). To the ethersolution was added a 10 weight percent aqueous hydrochloric acidsolution (about 400 milliliters) and the resulting oily hydrochloridewas washed with ether by decantation. Thereafter, ice was added to theoily hydrochloride, and the resulting aqueous mixture Was basified andextracted with diethyl ether.

The thus obtained ether extract was washed with water and a saturatedsodium chloride solution, dried by pass ing through sodium sulfate, andthen the ether evaporated. About 29 grams of oil were obtained.

The oil was chromatographed on silica gel (about 900 grams) using a 50volume percent ethyl acetate-cyclohexane solution and 1 volume percenttriethylamine as the eluant.

Elution was begun with 13 aliquots of about 250 milliliters each whichwere discarded. Additional elution with 4 aliquots of about 250'milliliters each gave crystalline fractions. These crystallinefractions, when crystallized from diethyl ether, produced about 7.2grams of crystals having a melting point of about 88 to 89 C. Themelting point was unchanged on recrystallization. The crystals wereidentified as 2,3-bis(p-methoxyphenyl)-1-pyrroline, obtained in about21% yield.

AnaIysis.-Calcd for C H NO (percent): C. 76.84: H. 6.81; N, 4.98. Found(percent): C. 76.70; H. 7.39; N, 5.06

U.V. absorption spectrum in ethanol.

\ 268 m (e=l8,200)

sh. 268 ma (5: 10,450) sh. 295 m (6 5,300)

In a manner similar to Example IV, other pyrrolines can be prepared bysuitably choosing the starting materials. The pyrrolines can, of course,be further converted to the corresponding pyrroles in a manner similarto Example VI. Typical illustrative starting materials and thepyrrolines that can be derived therefrom are compiled in Table I below:

TABLE L ILLUST RAIIVE FY RROLINES Starting materials End productNitromethane and 1,2-bis(p-butoxy- 2,3-l)is(p -liut0xyphenyl)-1-phenyl)-3-diethylamino-l-propanone. pyrrolme.

Nitromethane and 1,2-bis(o-ethoxy-2,3-bis(o-eth0xyphenyl)-lpl1enyl)-3-dibutylamino-l-propanone. pyrroliue.

Nitrcmethanc and l,2-bis(m-propoxy-2,3-bis(m-propoxyphenyl)-lphenyl)-3-dimethylamino-l-propanono.pyl'roliue.

Z-(p-butoxyphenyl)-3-(pmethoxyphenyD-lp yrroline.

2-(m-ethoxyphenyl)3-(0- propoxyphen yl)-1- p yrroline.

.Hp-tert .-butoxyphen yl) -3- (p-butox; pheuyl)1- pyrroline.

Nitromethaue and l-(p butoxyphenyll-z- (pmethoxyphen yl)-3-diethylamino-lpropanone.

Nitromethane and l-(m-ethoxyphenyl)-2-(o-propoxyphenyl)-3-dipr0pylaminc-L propauone.

N itroniethane and l-(p-tertrbutoxyphenyl)-2(p-but0xyphenyl)-3-dimethylamino-l-propanone.

EMMPLE V Preparation of 2,3-bis(p-methoxyphenyl)-1-pyrrolinehydrochloride 8 EXAMPLE v1 Preparation of2,3-bis(p-methoxyphenyl)pyrrole A mixture was prepared from 0.8 g. ofcrude 2,3-bis (pmethoxyphenyl)-1-pyrroline (i.e., not purified bychromatography), 5 weight percent of palladium-on-carbon catalyst (about0.8 gram), and Decalin (about 10 milliliters). This mixture was placedin a suitable reaction vessel and refluxed for about 6.5 hours.

Thereafter, the resulting admixture was cooled and chloroform was addedthereto to dissolve an oil which had separated during the refluxing, andthe resulting solution was then filtered through diatomaceous earth. Thefiltrate was washed with a 10 weight percent aqueous hydrochloric acidsolution, water, and a saturated sodium chloride solution, and thendried by passing through sodiurn sulfate. Thereafter, the filtrate wasevaporated at a pressure of about 0.1 mm. of Hg and at room temperature.About 0.7 gram of an oil was obtained as a residue.

The obtained oil was dissolved in methylene chloride and chromatographedon silica gel (about 42 grams). Elution with methylene chloride (about45 milliliters) gave about 0.22 gram of oil which was thenrechromatographed on silica gel (about 22 grams). Subsequent elutionwith a 10 volume percent ethyl acetate-cyclohexane solution (7 aliquots,about 10 milliliters each) gave about 0.07 gram of an oil which wasdiscarded. Further elution with another 10 milliliter aliquot produced0.138 gram of a product which was identical to the end product obtainedin Example III, i.e., 2,3-bis(p-methoxyphenyl)pyrrole. as established bythe comparison of U.V., I.R., and NMR spectra.

1 claim:

1. A bis(alkoxyphenyl)pyrrole represented by the structural formulaReferences Cited Szmuszkovicz ct al.: T. Med. Chem., v01. 9, pp. 527-351966).

ALEX MAZEL. Primary Examiner J. A. NARCAVAGE, Assistant Examiner US. Cl.X.R.

